Vinca alkaloids, originally isolated from the leaves of the periwinkle plant [Vinca rosea Linn., now Cantharanthus roseus (L.) G. Don] [Noble et al., Ann. N. Y. Acad. Sci. 1958 76:882-894; Noble, Lloydia 1964 27:280-281; Svoboda et al., J. Am. Pharm. Assoc. Sci. Ed. 1959 48:659-666] are a family of indole-indoline dimeric compounds that contain a four-ring system containing an indole linked to a five-ring system containing an indoline. Vinca alkaloids can be viewed as a hydration product of the coupling of vindoline with catharanthine. [See, Ishikawa et al., J. Am. Chem. Soc. 2008, 130:420; Ishikawa et al., J. Am. Chem. Soc. 2009, 131:4904.] That hydration provides the 21′-hydroxyl group that is present in vinblastine (1), vincristine (2) and vindestine (1a), below.
Vinblastine and vincristine are the most widely recognized members of the vinca alkaloids as a result of their clinical use as antitumor drugs, and their discovery represent one of the earliest important contributions that plant-derived natural products have made to cancer chemotherapy. [Neuss et al., In The Alkaloids; Brossi et al. Eds.; Academic: San Diego, 1990 37:229-240; Pearce, In The Alkaloids; Brossi et al. Eds.; Academic: San Diego, 1990 37:145-204; Kuehne, In The Alkaloids; Brossi et al. Eds.; Academic: San Diego, 1990 37:77-132.] In particular, those two natural alkaloids, vinblastine and vincristine, are important clinical agents and are used in combination therapies for treatment of Hodgkin's disease, testicular cancer (80% cure rate), ovarian cancer, breast cancer, head and neck cancer, and non-Hodgkin's lymphoma (vinblastine) or are used in the curative treatment regimes for childhood lymphocytic leukemia and Hodgkin's disease (vincristine). The semi-synthetic vinca alkaloid vindesine (1a), a derivative of vinblastine, is used to treat lung cancer and acute leukemia and less often for melanoma, and breast cancer. [Goodman & Gilman's The Pharmaceutical Basis of Therapeutics, Hardman et al. Eds., 9th ed. McGraw-Hill, 1257-1260, 1996.] The limitation to their continued clinical
 R1R2R3Vinblastine (1)—CH3 Vincristine (2) Vindesine (1a)—CH3—OHuse is the instances of treatment relapse with the emergence of tumor resistance derived from overexpression of P-glycoprotein (Pgp), a cell surface drug efflux transporter that lowers intracellular concentrations of many chemotherapeutic drugs including vinblastine and vincristine.
Vinblastine and vincristine were among the first small molecules shown to bind tubulin and to inhibit microtubule formation and mitosis. [Neuss et al., In The Alkaloids; Brossi et al. Eds.; Academic: San Diego, 1990 37:229-240; Pearce, In The Alkaloids; Brossi et al. Eds.; Academic: San Diego, 1990 37:145-204; Kuehne, In The Alkaloids; Brossi et al. Eds.; Academic: San Diego, 1990 37:77-132; Fahy, Curr. Pharm. Design 2001, 7:1181-1197; Potier, J. Nat. Prod. 1980 43:72-86; Kutney, Acc. Chem. Res. 1993 26:559-566; Miyazaki et al., Org. Lett. 2007 9:4737-4740.] Due to their clinical importance, low natural abundance, and structural complexity, they have been the subject of extensive and continuing biological and synthetic investigations. [Fahy, Curr. Pharm. Design 2001, 7:1181-1197; Potier, J. Nat. Prod. 1980 43:72-86; Kutney, Acc. Chem. Res. 1993 26:559-566; Miyazaki et al., Org. Lett. 2007 9:4737-4740; Noble et al., Ann. N. Y. Acad. Sci. 1958 76:882-894; Noble, Lloydia 1964 27:280-281; Svoboda et al., J. Am. Pharm. Assoc. Sci. Ed. 1959 48:659-666; Langlois et al., J. Am. Chem. Soc. 1976 98:7017-7024; Kuehne et al., J. Org. Chem. 1991 56:513-528; Bornmann et al., J. Org. Chem. 1992 57:1752-1760; Yokoshima et al., J. Am. Chem. Soc. 2002 124:2137-2139; Kuboyama et al., Proc. Natl. Acad. Sci. USA 2004 101:11966-11970; Ishikawa et al., J. Am. Chem. Soc. 2008 130:420-421; Ishikawa et al., J. Am. Chem. Soc. 2009 131:4904-4916.]
The vinca alkaloids share a common binding site on tubulin. The relative overall affinities for beta-tubulin binding are vincristine>vinblastine>vinorelbine>vinflunine, but there is no significant difference in the affinity of all four drugs for tubulin heterodimers. Vinflunine is not very potent in vitro yet is active in vivo, and this has been attributed to its superior cellular uptake.
Although these compounds are active in inhibiting the growth of cancerous cells, there are also differences in the profile of efficacy of vinca alkaloids. Vincristine has found wide use in the treatment of hematologic malignancies including leukemias and lymphomas. It is also widely used in pediatric solid tumors and, in the past, in small cell lung cancer. Vinblastine is an important component of the combination regimen that is curative for testicular cancer. Vindesine is used in the treatment of leukemia, lymphoma, melanoma, breast cancer, and lung cancer. Vinorelbine is quite different and has found use mainly in breast cancer and non-small cell lung cancer. Structural formulas for vinblastine, vincristine and vindesine are shown below.

Cellular growth inhibition data against a leukemia cell line (L1210), a colorectal carcinoma cell line (HCT116) and a vinblastine-resistant colorectal carcinoma cell line (HCT116/VM46) for vinblastine and initial C20′-vinblastine analogues were reported by the present inventor and co-workers in Leggans et al., Org. Lett. 2012 14:1428-1431, and are illustrated below.
 CompoundIC50 (nM)X =L1210HCT116HCT116/VM46OH6.06.8600H5060600N36706905500TEMPO400038005600SCN5605502900NH2640600>10000NHCHO65856500NHCOCH365907500NHCOCF36606908100NHCO2CH350752600NHCONHCOCCl3456.01600NHCONH2407.54400NHCSNH2557.72000NCS5905307000
The present inventor and co-workers reported the total synthesis of vinblastine [Ishikawa et al., J. Am. Chem. Soc. 2008 130:420-421; Ishikawa et al., J. Am. Chem. Soc. 2009 131:4904-4916] and its extension to the total synthesis of related natural products including vincristine and key analogues that utilizes a one-pot, two-step, biomimetic Fe(III)-promoted single electron oxidative coupling of catharanthine and vindoline and a subsequent Fe(III)/NaBH4-mediated in situ alkene oxidation to generate vinblastine directly. [Ishikawa et al., J. Am. Chem. Soc. 2006 128:10596-10612; Elliott et al., J. Am. Chem. Soc. 2006 128:10589-10595; Choi et al., Org. Lett. 2005 7:4539-4542; Yuan et al., Org. Lett. 2005 7:741-744; Wilkie et al., J. Am. Chem. Soc. 2002 124:11292-11294; Va et al., J. Am. Chem. Soc. 2010 132:8489-8495; Sasaki et al., J. Am. Chem. Soc. 2010 132:13533-13544; Kato et al., J. Am. Chem. Soc. 2010 132:3685-3687; Bioorg. Med. Chem. Lett. 2010 20:6408-6410; Gotoh et al., ACS Med. Chem. Lett. 2011 2:948-952; Gotoh et al., J. Am. Chem. Soc. 2012:134:13240-13243.]
Recently, the inventor and co-workers detailed the results of investigation of the Fe(III)/NaBH4-mediated free radical oxidation of the anhydrovinblastine trisubstituted alkene used to introduce the vinblastine C20′-tertiary alcohol [Ishikawa et al., J. Am. Chem. Soc. 2009 131:4904-4916], extending the reaction to provide a simple method for direct functionalization of unactivated alkenes. [Leggans et al., Org. Lett. 2012, 14:1428-1431; Barker et al., J. Am. Chem. Soc. 2012, 134:13588-13591.] In those studies, the broad alkene substrate scope was defined, the exclusive Markovnikov addition regioselectivity was established, the excellent functional group tolerance was revealed, alternative free radical traps were introduced, the Fe(III) salt and initiating hydride source were examined, and remarkably mild reaction conditions (0-25° C., 5-30 minutes) were introduced that are relatively insensitive to the reaction parameters.
The interest in this Fe(III)/NaBH4-mediated reaction emerged not only from its use in accessing vinblastine, but the opportunity it presented for the late-stage, divergent [Boger et al., J. Org. Chem. 1984, 49:4050-4055] preparation of otherwise inaccessible vinblastine analogues incorporating alternative C20′-functionality. Although this site is known to be critical to the properties of vinblastine [Borman et al., In The Alkaloids; Brossi, A., Suffness, M., Eds.; Academic: San Diego, 1990 37:133-144] and is found deeply embedded in the tubulin bound complex [Gigant et al., Nature 2005 435:519-522], the prior exploration of C20′-substituent effects has been limited to semi-synthetic O-acylation of the C20′-alcohol or its elimination and subsequent alkene reduction or superacid-catalyzed additions. [Miller et J. Med. Chem. 1977 20:409-413; Miller et al., Ger Patent 2753791 (Chem. Abstr. 1978 89:129778); Gerzon et al., Eur. Patent 55602 (Chem. Abstr. 1982 97:163310); Duflos et al., Curr. Med. Chem. Anti-Cancer Agents 2002 2:55-75.] These earlier reactions invariably led to substantial reductions in biological potency of the resulting derivative, albeit with examination of only a limited number of key analogues.
Consequently, in the course of the development of the Fe(III)/NaBH4-mediated alkene functionalization reaction, its use was extended to the preparation of a series of key vinblastine analogues bearing alternative C20′-functionality. Those of initial interest included the C20′-azide and amine, both of which proved to be approximately 100-fold less potent than vinblastine (1) and 10-fold less potent than 20′-deoxyvinblastine (3).
However, acylation of the C20′-amine improved activity 10-fold and installation of the unsubstituted C20′-urea or thiourea provided compounds that nearly matched the potency of vinblastine itself. As will be seen hereinafter, a systematic exploration of C20′-amine, -urea, and -thiourea derivatives of vinblastine have not only provided C20′-urea-based analogues that substantially exceed the potency of vinblastine, but also exhibit good activity against a Pgp-over-expressing, vinblastine-resistant tumor cell line. Just as remarkably and in contrast to expectations based on the steric constraints of the tubulin binding site surrounding the vinblastine C20′-center as depicted in the x-ray co-crystal structure of a tubulin bound complex [Gigant et al., Nature 2005 435:519-522], large C20′-urea derivatives are accommodated, exhibiting potent functional activity in cell-based proliferation assays and effectively binding tubulin.